A major emphasis of this project has been to define the relationship of exogenous hormones to subsequent cancer risk. Studies have assessed effects of both oral contraceptives and menopausal hormones. Given previous investigations that have shown excess risks of breast cancer associated with recent use of oral contraceptives among young women, further attention has focused on whether the elevations in risk were attributable to use of certain pills. This showed some support for higher risks among users of pills containing high doses of estrogens or progestins. Unique opportunities for analyzing effects of menopausal hormones derived from data from the follow-up study of participants in the Breast Cancer Detections Demonstration Project, a large nation-wide breast screening project. Using approaches similar to previous analyses for breast cancer risk, additional analyses related use of exogenous hormones to an elevated risk of ovarian cancer. These analyses showed risk to increase with years of use of hormones, particularly when the preparation used was unopposed estrogens. Relationships with endometrial cancer are being pursued with additional follow-up data. Also of interest is the relationship of breast implants to subsequent cancer risk. Breast cancer risk has been of concern, given that breast implants can interfere with the mammographic visualization of lesions. However, in a large retrospective study that we conducted, we found no evidence for an alteration in breast cancer risk. These patients also generally did not experience alterations in other cancer sites, although elevations were observed in the risk of lung and brain cancers, the explanation for which remains unclear. In a mortality analysis, implant patients had signficantly elevated risks of death from suicide, but other causes of death were similar to the general population. Currently underway are analyses of risk of connective tissue diseases related to breast implants. In addition, we are continuing to follow the cohort for mortality to determine whether previously observed patterns persist. A retrospective cohort study was also conducted to examine the effects on cancer risk of different causes of infertility and of different associated therapies. This study involved detailed abstraction of medical records of patients diagnosed as long ago as the 1960's and administration of questionnaires to obtained updated health information. A strength of the study was the detailed information collected on causes of infertility. Analyses showed that type of infertility (primary vs. secondary) was a more important predictor of cancer risk than specific causes of infertility. However, patients with endometriosis were at an especially high risk of developing ovarian cancer. In general, the study provided reassuring results regarding use of ovulation-inducing agents, showing no major increases in cancer risk relating to use of either clomiphene citrate or human menopausal gonadotropins. There were, however, slight increases in risk of both breast and ovarian cancers among the subjects followed for the longest periods of time (15 or 20+ years), supporting the need for additional monitoring of long-term effects of these agents. Separate interest has also focused on whether ovulation-inducing agents might affect the risk of cancer in children conceived following thier use. In a separate investigation in Denmark, which used record linkage efforts, generally reassuring results were provided. The only cancer site that showed any alteration was that of hematopoietic cancers occurring later in life. The elevation in risk for this tumor site, however, was based on small numbers, was non-significant, and appeared to relate more to underlying reasons for usage than to an effect of the medications. Recent cohort studies demonstrated reduced breast cancer risks among women with a history of fractures or low bone mineral density. The impact of the severity and timing of bone loss on risk has not yet been investigated, and the extent to which other risk factors (family history, anthropometric factors, physical activity, and exogenous hormones) modify the relationship with bone density is unknown. To elaborate on these research questions, we are conducting a follow-up study of over 20,000 postmenopausal women who volunteered for a clinical trial of the bone-enhancing drug alendronate. This large cohort includes extensive baseline information on major breast cancer risk factors, and thus is ideal for evaluating potential interactions with bone mineral density and the effects of bone mineral density on other cancer sites. The data collection phase of the study is nearly complete, and planned analyses will answer important questions about the relationship between bone density and cancer risk in postmenopausal women. A number of medical conditions have been suggested as predisposing to the risk of breast, endometrial and ovarian cancers, but most of these studies have relied on patients reports of these prior conditions. To obtain more precise information on the nature of these prior medical conditions, we have conducted a large case-cohort study in Denmark that involves access to details of the conditions as contained in medical records. Ongoing analyses are assessing relationships of cancer risk according to details of the prior diagnoses.